Nobel Laureates on Their Hunt for the Cure

Emily Willingham

December 09, 2020

This year's Nobel Prize in Medicine went to three scientists who discovered the hepatitis C virus. Harvey J. Alter (left), Michael Houghton (center), and Charles  M. Rice (right) were chosen for their achievement that led to the rapid development of life-saving antivirals.

Researchers have worked at record-breaking speed to not only identify and characterize the novel coronavirus, but also to develop potential vaccines; it is a race that another trio of scientists, awarded the 2020 Nobel Prize in Medicine, know well after their own decades-long marathon to crack the code of hepatitis C.

The RNA virus vexed researchers like Harvey J. Alter, Michael Houghton, and Charles M. Rice for years. Unlike today's parallel sequencing and PCR, screening at the time was tedious, painstaking. But they were all in for some big highs, some dead-ends, and a little inspiration by way of author Lewis Carroll.

"Our undertaking was a success," Alter told Medscape Medical News, "because everyone got on board." Investigators, the US Food and Drug Administration (FDA), and blood banks all worked together. It was a national effort, he adds.

The Laureates will share the $1 million prize that recognizes their achievement. This is the second time that scientists who have devoted their time to the pursuit of viral hepatitis have been honored.

Two main types of infectious hepatitis were identified in the 1940s. The first, hepatitis A, is transmitted by polluted water or food and generally has little long-term effect on the patient. The second, transmitted through blood and other bodily fluids, is a much more serious threat.

In the 1960s, Baruch Blumberg ascertained that blood-borne hepatitis was caused by an insidious virus — hepatitis B — which silently causes liver complications in otherwise healthy people years after infection. Blumberg's discovery led to the development of diagnostic tests and an effective vaccine; he was awarded the Nobel Prize in Physiology or Medicine in 1976.

At that time, Alter was working at the National Institutes of Health in Bethesda, Maryland, studying the occurrence of hepatitis in patients who had received blood transfusions. Globally, blood-borne hepatitis was causing more than a million deaths each year.

When screening began in 1969 to prevent people with hepatitis A or hepatitis B from donating blood, many recipients were spared from developing liver inflammation after transfusion. However, some people were still getting sick and researchers began to suspect that something dubbed "non-A, non-B" was lurking in donated blood.

As scientists were tracking it down in the micro world, public health officials and others tried to block the presumed virus in the macro world. In the United States, this meant changing blood-donation practices. When it became clear that as many as one in five transfusion recipients developed hepatitis, probably as the result of a virus, the blood donation system switched from being a paid enterprise to a volunteer activity.

It was anticipated that this would eliminate one source of the virus — users of street drugs — and it did; rates of transmission after transfusion dropped by half.

Watch the ceremonies here

By the 1980s, researchers had figured out that donors carrying the mysterious pathogen often had elevated levels of antibodies to the hepatitis B virus or elevated levels of alanine transaminase. Blood banks then began testing prospective donors and cut the incidence of non-A, non-B hepatitis by another half.

When Alter and his team got to work studying chimpanzees, they were able to confirm that the non-A, non-B agent was transmittable by blood transfusion. But the next step proved insurmountable. "People knew what the virus would look like if we found it, but we couldn't find it," Alter says.

"Then Chiron came along and cloned it," he recounts.

The tiny start-up company was housed in a few rented rooms in an abandoned plant in Emeryville, California. This is where Nobel Laureate Michael Houghton, PhD, and coworkers Qui-Lim Choo, PhD, and George Kuo, PhD, spent 7 years chasing the mystery pathogen. When every traditional method to pin it down failed, the team tried some nontraditional approaches.

They found success when they painstakingly cloned genomic fragments from the blood of an infected chimpanzee and then screened this library using serum isolated from affected patients. The hope was that antibodies in the serum samples would stick to the viral genetic material and create a signpost indicating its presence.

This "fishing expedition" was disappointing at first, said Choo, now vice president of research at Nansha Biologics Limited in Hong Kong. "We didn't catch any fish."

He likened the pursuit, which took place under growing pressure from upper management, to that in The Imitation Game, the film that depicted Alan Turing's effort to decrypt German intelligence messages for the British government during World War II.

The effort wasn't working out and the team was down. So to keep spirits up, Kuo shared a snippet of the Lewis Carroll poem The Hunting of the Snark. It just happened to encapsulate the frustrations of their pursuit while also encouraging perseverance: "For the Snark's a peculiar creature, that won't / Be caught in a commonplace way. / Do all that you know, and try all that you don't: / Not a chance must be wasted today!"

Hepatitis C investigators say a quote from The Hunting of the Snark helped inspire their search.

Those words motivated the team to keep going, to try different approaches and, ultimately, to find the hepatitis C virus, said Kuo, now retired.

During the tedious process of screening millions of clones, Choo spotted a single likely area on one of the plates that his "gut feeling" told him would contain the viral material. And it did. The pathogen — RNA packed in a lipid coat — was a member of the Flaviviridae family.

In 1989, the team reported that they'd identified a new flavivirus associated with post-transfusion hepatitis, and published their findings in Science. Later that year, an antibody test for it was described in Science by the team, which included Alter.

The success was a "fantastic feeling," mused Houghton, now a virologist at the University of Alberta in Edmonton, Canada. "I've often said that from 1989 to 1991, I was high just on the discovery." After that, "researchers and the pharmaceutical industry did a great job coming up with really effective antivirals."

"Mike, with his team, took 7 years to get this tiny little piece of viral genome, which reacted with convalescent patient serum, and used that to build up the sequence. That's where I come into it," said Charles Rice, professor of virology at The Rockefeller University in New York City, and the third scientist in the Nobel Prize–winning trio.

Pinpointing the Molecular Target

Charles Rice (right) in the laboratory with a student. Photo from the Rockefeller University.

The next step was to confirm that this was causing the hepatitis in patients who received blood transfusions. Over the course of several years, Rice and his colleagues at the Washington University School of Medicine in St. Louis engineered a version of the virus that retained its replicating capacity and injected it into chimpanzees. The animals developed hepatitis, confirming that this flavivirus was indeed the cause. More than 8 years after the virus was identified, scientists had proof of its infectiousness.

"We finally knew the structure of the viral genome," said Rice. "We showed that the sequence was sufficient to initiate infection and cause disease."

Those findings, published in 1997 in Science, were the key final step in the search for a molecular target for therapies and, maybe someday, a vaccine.

For the first time in history, hepatitis C can now be cured, raising hopes that the virus will be eradicated from the world population. But obstacles remain as the World Health Organization works toward its goal of eliminating hepatitis C–related disease by 2030.

Rates have actually risen in the United States as the opioid epidemic has taken hold because the virus is common in people who use street drugs and are at increased risk for behaviors that lead to transmission.

The prevalence of chronic hepatitis C now hovers around 1%. In 2019, it affected an estimated 3.8 million Americans, and more than 39,000 people died of hepatitis C–related causes. Of all deaths from liver cancer in 2019, 39% were attributable to hepatitis C.

This "silent killer" can take years to develop, which dampens the sense of immediacy to help, said Jean-Michel Piedagnel, director of the Drugs for Neglected Diseases nonprofit initiative.

People infected with hepatitis C are often part of marginalized groups. There isn't typically a common demographic factor to unite them in advocacy.

And even though treatment can cost as little as $200 in countries where generic drugs are available, money can still be an issue, Piedagnel pointed out.

The COVID-19 response shows how quickly health systems can evolve in a crisis and adapt. "If there is political will, means can be found, said Cary James, chief executive officer at the World Hepatitis Alliance.

The incredible speed of vaccine development for SARS-CoV-2 has impressed the Nobel Laureates, who have yet to see a vaccine for hepatitis C.

Houghton said he hopes this momentum will perpetuate new emergency filings for hepatitis C vaccines. If even a tiny fraction of the money that's gone into COVID-19 were used, Rice pointed out, "we'd have a hep C vaccine by now."

Emily Willingham is a freelance journalist and scientist with a bachelor's degree in English and a PhD in biology. She reports on health topics, including infectious disease and hepatology.

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